KR810000953B1 - Method for the preparation of 2'-(carboxymethoxy)-chalcones - Google Patents
Method for the preparation of 2'-(carboxymethoxy)-chalcones Download PDFInfo
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- KR810000953B1 KR810000953B1 KR7700273A KR770000273A KR810000953B1 KR 810000953 B1 KR810000953 B1 KR 810000953B1 KR 7700273 A KR7700273 A KR 7700273A KR 770000273 A KR770000273 A KR 770000273A KR 810000953 B1 KR810000953 B1 KR 810000953B1
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- Prior art keywords
- methyl
- ulcer
- butenyloxy
- compound
- gastric
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- LJAXJWSGQODKEC-UHFFFAOYSA-N 2-[2-(3-phenylprop-2-enoyl)phenoxy]acetic acid Chemical class OC(=O)COC1=CC=CC=C1C(=O)C=CC1=CC=CC=C1 LJAXJWSGQODKEC-UHFFFAOYSA-N 0.000 title claims description 3
- 238000000034 method Methods 0.000 title description 18
- 238000002360 preparation method Methods 0.000 title description 2
- -1 3-methyl-2-buteneoxy Chemical group 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 12
- ZCAMZJYDORGUOV-UHFFFAOYSA-N 4-(3-methylbut-2-enoxy)benzaldehyde Chemical compound CC(C)=CCOC1=CC=C(C=O)C=C1 ZCAMZJYDORGUOV-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- GFWRVVCDTLRWPK-UHFFFAOYSA-N sofalcone Chemical compound C1=CC(OCC=C(C)C)=CC=C1C=CC(=O)C1=CC=C(OCC=C(C)C)C=C1OCC(O)=O GFWRVVCDTLRWPK-UHFFFAOYSA-N 0.000 abstract 1
- 208000025865 Ulcer Diseases 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 231100000397 ulcer Toxicity 0.000 description 37
- 239000000243 solution Substances 0.000 description 25
- 241000700159 Rattus Species 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 208000007107 Stomach Ulcer Diseases 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 210000002784 stomach Anatomy 0.000 description 11
- 230000036269 ulceration Effects 0.000 description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000002265 prevention Effects 0.000 description 9
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 229960001138 acetylsalicylic acid Drugs 0.000 description 8
- 230000035876 healing Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 235000005513 chalcones Nutrition 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000003628 erosive effect Effects 0.000 description 7
- 201000005917 gastric ulcer Diseases 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 150000001789 chalcones Chemical class 0.000 description 6
- 208000000718 duodenal ulcer Diseases 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 4
- FEUFLYNZOILPFG-UHFFFAOYSA-N ethyl 2-phenacyloxyacetate Chemical compound CCOC(=O)COCC(=O)C1=CC=CC=C1 FEUFLYNZOILPFG-UHFFFAOYSA-N 0.000 description 4
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 229960003151 mercaptamine Drugs 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- ZWVHTXAYIKBMEE-UHFFFAOYSA-N 2-hydroxyacetophenone Chemical compound OCC(=O)C1=CC=CC=C1 ZWVHTXAYIKBMEE-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 206010042220 Stress ulcer Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002575 gastroscopy Methods 0.000 description 2
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 description 2
- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 description 2
- 235000008718 isoliquiritigenin Nutrition 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- AIFRLZKCLIPEMC-UKTHLTGXSA-N (e)-1-[2,4-dihydroxy-3-(3-methylbut-2-enyl)phenyl]-3-[2,2-dimethyl-8-(3-methylbut-2-enyl)chromen-6-yl]prop-2-en-1-one Chemical compound C=1C=2C=CC(C)(C)OC=2C(CC=C(C)C)=CC=1\C=C\C(=O)C1=CC=C(O)C(CC=C(C)C)=C1O AIFRLZKCLIPEMC-UKTHLTGXSA-N 0.000 description 1
- PIAPWPAWQGDOMN-UHFFFAOYSA-N 1-[2,4-dihydroxy-6-methoxy-3-(5-methyl-2-prop-1-en-2-ylhex-4-enyl)phenyl]-3-(2,4-dihydroxyphenyl)prop-2-en-1-one Chemical compound COC1=CC(O)=C(CC(CC=C(C)C)C(C)=C)C(O)=C1C(=O)C=CC1=CC=C(O)C=C1O PIAPWPAWQGDOMN-UHFFFAOYSA-N 0.000 description 1
- UMLLUUJWDQUBMQ-UHFFFAOYSA-N 1-[2-methoxy-4-(3-methylbut-2-enoxy)phenyl]-3-[4-(3-methylbut-2-enoxy)phenyl]prop-2-en-1-one Chemical compound COC1=CC(OCC=C(C)C)=CC=C1C(=O)C=CC1=CC=C(OCC=C(C)C)C=C1 UMLLUUJWDQUBMQ-UHFFFAOYSA-N 0.000 description 1
- JKXQKGNGJVZKFA-UHFFFAOYSA-N 1-chloro-3-methylbut-2-ene Chemical compound CC(C)=CCCl JKXQKGNGJVZKFA-UHFFFAOYSA-N 0.000 description 1
- WHPLQIKCSLNSBR-UHFFFAOYSA-N 2,4-bis(3-methylbut-2-enoxy)benzaldehyde Chemical compound CC(C)=CCOC1=CC=C(C=O)C(OCC=C(C)C)=C1 WHPLQIKCSLNSBR-UHFFFAOYSA-N 0.000 description 1
- QMYNUASZONCCEI-UHFFFAOYSA-N 2-(3-methylbut-2-enoxy)benzaldehyde Chemical compound CC(C)=CCOC1=CC=CC=C1C=O QMYNUASZONCCEI-UHFFFAOYSA-N 0.000 description 1
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 1
- WLOHADCBIYOCBF-UHFFFAOYSA-N 3-[2-(3-methylbut-2-enoxy)phenyl]-1-phenylprop-2-en-1-one Chemical compound CC(C)=CCOC1=CC=CC=C1C=CC(=O)C1=CC=CC=C1 WLOHADCBIYOCBF-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 239000005749 Copper compound Substances 0.000 description 1
- 206010062532 Erosive duodenitis Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- YNWXJFQOCHMPCK-UHFFFAOYSA-N Isoliquiritin Natural products OC1C(O)C(O)C(CO)OC1OC(C=C1)=CC=C1C=CC(=O)C1=CC=C(O)C=C1O YNWXJFQOCHMPCK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- AIFRLZKCLIPEMC-UHFFFAOYSA-N Sophoradochromene Natural products C=1C=2C=CC(C)(C)OC=2C(CC=C(C)C)=CC=1C=CC(=O)C1=CC=C(O)C(CC=C(C)C)=C1O AIFRLZKCLIPEMC-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000001467 acupuncture Methods 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 150000001788 chalcone derivatives Chemical class 0.000 description 1
- 230000007665 chronic toxicity Effects 0.000 description 1
- 231100000160 chronic toxicity Toxicity 0.000 description 1
- 150000001880 copper compounds Chemical class 0.000 description 1
- 229940097265 cysteamine hydrochloride Drugs 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000000245 forearm Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- PPZMYIBUHIPZOS-UHFFFAOYSA-N histamine dihydrochloride Chemical compound Cl.Cl.NCCC1=CN=CN1 PPZMYIBUHIPZOS-UHFFFAOYSA-N 0.000 description 1
- 229960000645 histamine hydrochloride Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- YNWXJFQOCHMPCK-LXGDFETPSA-N isoliquiritin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC(C=C1)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O YNWXJFQOCHMPCK-LXGDFETPSA-N 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000734 parasympathomimetic agent Substances 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000006100 radiation absorber Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
Abstract
Description
본 발명은 항위궤양 및 항십이지궤양치료제로서 유용한 신규의 2'-(카복시메톡시)-칼콘류의 제조방법에 관한 것으로서, 좀더 상세히 말하면 본 발명은 다음 일반식(1)로 표시된 신규의 2'-(카복시메톡시)-칼콘의 제조방법에 관한 것이다.The present invention relates to a method for preparing novel 2 '-(carboxymethoxy) -chalcones useful as anti-gastric and anti-duodenal ulcer therapeutic agents. More specifically, the present invention relates to a novel 2' represented by the following general formula (1): It relates to a method for preparing-(carboxymethoxy) -chalcone.
식중,Food,
X1,X2, 및 X3의 1-2개는 3-메틸-2- 부테닐옥시이고,1-2 of X 1 , X 2 , and X 3 are 3-methyl-2-butenyloxy,
나머지는 수소이다.The rest is hydrogen.
종래에 알려진 각종의 칼콘류는 산화방지제, 방사선흡수제 및 감미제와 같은 용도를 가지고 있음이 보고되어 있다. 그리고 일부의 칼콘류는 약리학적으로 활성물질, 예컨대 진통제, 항염증제, 항균제 및 혈관 확장제로서 보고되어 있다.It is reported that various chalcones known in the art have applications such as antioxidants, radiation absorbers and sweeteners. And some chalcones are reported pharmacologically as active substances such as analgesics, anti-inflammatory agents, antimicrobials and vasodilators.
이외에 항위궤양작용을 가진 칼콘류에 관해서는 다음의 문헌, 즉 일본특허 제623,498호(Sophoradochro-mene), 일본특허 제691,783호(2,2', 4,4'-테트라하이드록시-6'-메톡시-3'-(5-메틸-2 이소프로페닐헥스-4-에닐)-칼콘, Arzneimittel Forschung 17,1544(1967)(Isoliquiritigenin)및 미국특허 제3,928,421호(항위궤양제 칼콘에테르)에 발표되어 있다.In addition, regarding the chalcones having an anti-gastric action, Japanese Patent No. 623,498 (Sophoradochro-mene) and Japanese Patent No. 691,783 (2,2 ', 4,4'-tetrahydroxy-6'- Methoxy-3 '-(5-methyl-2 isopropenylhex-4-enyl) -chalcone, Arzneimittel Forschung 17,1544 (1967) (Isoliquiritigenin) and U.S. Patent No. 3,928,421 (anti-ulcer chalconethers) It is.
상술한 일본특허에는 식물로 부터 동화합물의 추출방법이 발표되어 있는데 이들 방법은 공정이 복잡하고, 수율과 순도가 낮은 결점이 있으며, 식물로 부터 추출된 이소리퀴리틴(Isoliquiritin)을 가수분해에 의해 얻어진 이소리퀴리티게닌 (Isoliquiritigenin)은 순도가 낮다.The above-mentioned Japanese patent discloses a method for extracting a copper compound from plants, which has a complicated process, low yield and low purity, and hydrolysis of Isoliquiritin extracted from plants. The obtained Isoliquiritigenin is of low purity.
상술한 칼콘류는 모두 친수성기가 몇개만 있거나 전혀 없어서 생체내에서 흡수율을 기대하기가 어렵다. 이제까지 항십이지궤양작용을 가진 칼콘유도체는 발견된 일이 없었다.All of the aforementioned chalcones have few hydrophilic groups or no hydrophilic groups, so it is difficult to expect absorption in vivo. So far, no chalcone derivatives with antiduodenal ulcer activity have been found.
따라서 본 발명의 목적은 우수한 항위궤양 및 항십이지궤양작작용을 가질뿐만 아니라, 생체내에서 흡수율이 높고 급성 및 만성독성이 적은 신규의 칼콘류를 제공함에 있다.Therefore, an object of the present invention is to provide a novel chalcones having a good anti-ulcer and anti-duodenal ulceration action, as well as high absorption rate and low acute and chronic toxicity in vivo.
또한 본 발명의 목적은 간편하고 편리한 방법, 다시 말해서, 제품생산에 용이하게 이용할 수 있는 방법에 의하여 신규의 유용한 칼콘류를 제공함에 있다.It is also an object of the present invention to provide a novel useful chalcones by a simple and convenient method, that is, a method that can be easily used for production.
본 발명의 방법은 다음 일반식(2)의 화합물과 다음 일반식(3)의 화합물을 반응시켜 일반식(1)의 목적하는 화합물을 제조하는 것으로 구성되어 있다.The method of this invention consists of making the target compound of General formula (1) react with the compound of following General formula (2), and the compound of following General formula (3).
상기 일반식(2) 및 일반식(3)에서,In the general formula (2) and formula (3),
X1, X2및 X3는 상술한 바와 같으며,X 1 , X 2 and X 3 are as described above,
R는 수소 및 탄소원자수 1-6개의 저급알킬로 부터 선택된 기이다.R is a group selected from hydrogen and lower alkyl of 1-6 carbon atoms.
본 발명의 방법에서 일반식(2)의 화합물과 일반식(3)의 화합물과의 반응은 메틴올, 에탄올, 아세톤, 헥산, 벤젠 및 디메틸포름아미드와 같은 유기용매에 용해시킨 일반식(2)와 일반식(3)의 화합물용액에 수산화나트륨, 수산화칼리움, 탄산나트륨, 탄산칼리움, 소디움 메톡사이드 및 소디움 에톡사이드와 같은 알카리를 가한후, 이 혼합물을 0-100℃에서 수시간동안 교반하여 행한다. 생성된 일반식(1)의 화합물은 모액으로 부터 분리하여 재결정에 의해 정제할 수 있다.In the process of the present invention, the reaction of the compound of formula (2) with the compound of formula (3) is carried out in the general formula (2) dissolved in organic solvents such as methol, ethanol, acetone, hexane, benzene, and dimethylformamide. And alkali, such as sodium hydroxide, calcium hydroxide, sodium carbonate, calcium carbonate, sodium methoxide, and sodium ethoxide, were added to the compound solution of formula (3), and the mixture was stirred at 0-100 ° C. for several hours. Do it. The resulting compound of formula (1) can be purified by recrystallization from the mother liquor.
일반식(2)의 화합물은 2-하이드록시 아세토페논 또는 2-하이드록시-4-(3-메틸-2-부테닐옥시)과 할로게노초산 또는 할로게노초산 저급알킬 에스테르를 반응시켜 제조하며, 일반식(3)의 화합물은 2-하이드록시벤즈알데히드, 4-하이드록시벤즈알데히드 또는 2,4-디하이드록시벤즈알데히드와 1-할로게노-3-메틸-2-부텐을 반응시켜 제조할 수 있다.The compound of formula (2) is prepared by reacting 2-hydroxy acetophenone or 2-hydroxy-4- (3-methyl-2-butenyloxy) with halogenoacetic acid or halogenoacetic acid lower alkyl ester, The compound of formula (3) may be prepared by reacting 2-hydroxybenzaldehyde, 4-hydroxybenzaldehyde or 2,4-dihydroxybenzaldehyde with 1-halogeno-3-methyl-2-butene.
일반식(1)로 표시된 화합물의 장점, 즉 생체내에서의 높은 흡수율, 우수한 항위궤양 및 항십이지궤양작용 및 저독성은 칼콘골격구조, 2'-카복시메톡시기 및 1개 또는 2개의 3-메틸-2-부테닐옥시기의 조합에 의하여 기여되는 것으로 사료된다. 특히, 2'-카복시메톡시기는 생체내에서의 높은 흡수율에 기여한다.The advantages of the compound represented by formula (1), namely, high absorption rate, good anti-gastric and anti-duodenal ulceration and low toxicity in vivo, include a chalcone skeletal structure, a 2'-carboxymethoxy group and one or two 3-methyl- It is thought to be contributed by the combination of 2-butenyloxy groups. In particular, the 2'-carboxymethoxy group contributes to a high rate of absorption in vivo.
일반식(1)의 화합물은 다음 표 1에 나타난 바와같이, 2'-카복시메톡시기를 갖지 않은 화합물보다 쥐에게서 높은 흡수율을 나타냈다.The compound of formula (1) showed higher absorption rate in rats than the compound without 2'-carboxymethoxy group, as shown in Table 1 below.
일반식(1)의 화합물은 쥐 또는 모르모트에서 나타나는 각종 형태의 위궤양에 대하여 우수한 치료효과 또는 예방효과를 나타냈다. 즉, 본 발명의 화합물은 초산의 주사로 유발된 만성 위궤양(초산궤양)의 치유과정을 촉진하였으며, 유문부(幽門部, 세이스궤양: shay's ulcer)의 결찰(結紮)이나 억류 및 수침(水沈)에 의해 동물에 스트레스를 가하여 형성된 궤양(스트레스궤양) 및 미란을 억제하였고, 또한 아스피린의 투여에 의해 유발된 궤양(아스피린 궤양) 및 미란을 억제하였다. 더우기, 일반식(1)의 화합물은 히스타민의 주사로 유발된 급성 위궤양(히스타민 위궤양)의 치유과정을 촉진하였으며, 시스테아만의 투여로 유발된 궤양(시스테아민 궤양)과 미란을 억제하였다(시스테아민의 투여로 유발된 위궤양뿐만 아니라, 십이지궤양 및 미란을 억제하였음). 이러한 효과는 모두 다음 표 1에 나타난 바와같이 2'-카복시메톡시기를 갖지 않은 화합물에서는 발견되지 않았다.The compound of formula (1) showed an excellent therapeutic or preventive effect against various types of gastric ulcers in rats or morphites. That is, the compounds of the present invention promoted the healing process of chronic gastric ulcers (acetic acid ulcers) induced by injection of acetic acid, and ligation or detention and immersion of the pyloric ulcers (shay's ulcer). Ulcers (stress ulcers) and erosions formed by stressing the animals were suppressed, and ulcers (aspirin ulcers) and erosions caused by administration of aspirin were also suppressed. Moreover, the compound of formula (1) promoted the healing process of acute gastric ulcers (histamine gastric ulcers) induced by injection of histamine and suppressed ulcers (cysteamine ulcers) and erosion induced by administration of cysteaman alone ( Inhibited gastric ulcer caused by administration of cysteamine, as well as duodenal ulcer and erosion). All these effects were not found in compounds without 2'-carboxymethoxy groups as shown in Table 1 below.
일반식(1)의 화합물은 급성 및 만성위궤양의 양자에 모두 유효하며, 손상된 위점막조직의 회복을 촉진하고, 위궤양의 발생 또는 재발을 방지하며, 기왕의 위궤양에 우수한 치유효과를 나타내며, 또한 십이지궤양에 유효하다. 더우기, 본 발명의 화합물은 염산 또는 펩신과 같은 궤양에 대한 공격인자의 분비에 대하여 억압작용이 약하지만, 부교감신경억제제의 투여시에 나타나는 것과 같은 부작용이 없다.The compound of formula (1) is effective for both acute and chronic gastric ulcers, promotes repair of damaged gastric mucosal tissues, prevents the occurrence or recurrence of gastric ulcers, and has an excellent healing effect on previous gastric ulcers. It is available for ulcers. Moreover, the compounds of the present invention have a weak suppressive effect on the secretion of attackers against ulcers such as hydrochloric acid or pepsin, but do not have side effects such as those which occur when administration of parasympathetic agents.
일반적인 약리작용으로서, 원하지 않는 부작용은 본 발명의 투여에 의해 중추신경계통과 자율신경계통에서 나타난 일이 없다.As a general pharmacological action, unwanted side effects do not occur in the central nervous system and autonomic nervous system by administration of the present invention.
일반식(1)로 표시된 화합물의 독성은 극히 적으며, 경구적으로 체중 kg당 8g을 투여할때 마우스, 쥐 및 개에게서 96시간내에 치사가 없었으며, 30일간 경구적으로 체중 kg당 1g을 투여할때 부작용이 나타나지 않았다. 따라서 본 발명의 화합물은 아무 부작용의 수반없이 장기간 안전하게 투여할 수 있다.The toxicity of the compound represented by the formula (1) is extremely low, and there was no lethal death in 96 hours in mice, rats, and dogs when orally administered 8 g / kg body weight, and 1 g / kg body weight orally for 30 days. No adverse effects were seen with the administration. Thus, the compounds of the present invention can be safely administered for a long time without any side effects.
이하 실시예에 의하여 본 발명을 상세히 설명하면 다음과 같다. 다음 참고 실시예는 일반식(2)와 일반식(3)의 화합물의 합성법을 설명한 것이다.Hereinafter, the present invention will be described in detail with reference to the following examples. The following reference examples illustrate the synthesis of compounds of general formula (2) and general formula (3).
[참고 실시예 1]Reference Example 1
아세톤 20ml에 용해시킨 2-하이드록시-4-(3-메틸-2-부테닐옥시)-아세토페논 1.1g의 용액에 수산화칼리움 0.3g을 가하고, 이 혼합물에 브로모초산 에틸에스테르 1.0g을 교반하면서 적가한 후, 혼합물을 실온에서 2시간동안 교반하여 반응혼합물을 회염산으로 회석하고, 에테르로 3회 추출한 다음, 에테르층을 물로 충분히 세척하여 황산나트륨상에서 건조하고 에테르를 증발시켜 잔사를 에테르-석유벤젠으로 부터 재결정시킨 결과 2-(에톡시카보닐메톡시)-4-(3-메틸-2-부테닐옥시)-아세토페논 1.4g이 얻어졌다. 융점 : 60-62℃0.3 g of potassium hydroxide was added to a solution of 1.1 g of 2-hydroxy-4- (3-methyl-2-butenyloxy) -acetophenone dissolved in 20 ml of acetone, and 1.0 g of bromoacetic acid ethyl ester was added to the mixture. After dropwise addition while stirring, the mixture was stirred at room temperature for 2 hours, the reaction mixture was distilled with dichloric acid, extracted three times with ether, the ether layer was washed with water sufficiently, dried over sodium sulfate and the ether was evaporated to give the residue an ether-. Recrystallization from petroleum benzene gave 1.4 g of 2- (ethoxycarbonylmethoxy) -4- (3-methyl-2-butenyloxy) -acetophenone. Melting Point: 60-62 ℃
[참고 실시예 2]Reference Example 2
상기 실시예 1에 기술된 방법에 따라 브로모초산 에틸에스테르 대신에 클로로초산 메틸에스테르를 사용하여 처리한 결과 2-(메톡시카보닐메톡시)-4-(3-메틸-2-부테닐옥시)-아세토페논 1.3g이 얻어졌다.융점 : 80-82℃Treatment with chloroacetic acid methyl ester instead of bromoacetic acid ethyl ester according to the method described in Example 1 above resulted in 2- (methoxycarbonylmethoxy) -4- (3-methyl-2-butenyloxy) 1.3 g of acetophenone was obtained. Melting point: 80-82 ° C.
[참고 실시예 3]Reference Example 3
상기 실시예 1에 기술된 방법에 따라 브로모초산 에틸에스테르 대신에 브로모초산을 사용하여 처리한 결과 2-(카복시메톡시)-4-(3-메틸-2-부테닐옥시)-아세토페논 0.9g이 얻어졌다. 융점 : 138-140℃Treatment with bromoacetic acid instead of bromoacetic acid ethyl ester according to the method described in Example 1 above resulted in 2- (carboxymethoxy) -4- (3-methyl-2-butenyloxy) -acetophenone 0.9 g was obtained. Melting Point: 138-140 ℃
[참고 실시예 4]Reference Example 4
아세톤 40ml에 용해시킨 2-하이드록시 아세토페논 10g의 용액에 탄산칼리움 12g을 가하고, 이 혼합물을 실온에서 1시간동안 교반한후 브로모초산 에틸에스테르 14g을 교반하면서 적가하여 3시간동안 교반하고, 반응혼합물을 여과하여 아세톤을 증발시킨 다음, 잔사를 에테르로 추출하고, 에테르를 증발하여 얻어진 잔사를 석유에테르로부터 재결정시킨 결과 2-(에톡시카보닐메톡시)-아세토페논 9.7g이 얻어졌다.12 g of calcium carbonate was added to a solution of 10 g of 2-hydroxy acetophenone dissolved in 40 ml of acetone, the mixture was stirred at room temperature for 1 hour, and 14 g of bromoacetic acid ethyl ester was added dropwise with stirring, followed by stirring for 3 hours. The reaction mixture was filtered to evaporate acetone, the residue was extracted with ether, and the residue obtained by evaporating the ether was recrystallized from petroleum ether to give 9.7 g of 2- (ethoxycarbonylmethoxy) -acetophenone.
융점 : 33-35℃Melting Point: 33-35 ℃
[참고 실시예 5]Reference Example 5
아세톤 200ml에 용해시킨 2,4-디하이드록시벤즈알데히드 5g의 용액에 탄산칼리움 15g을 가하고, 이 혼합물을 실온에서 20분간 교반한후, 3-메틸-2-부테닐클로라이드 12g을 적가하여 3시간동안 교반한 다음, 반응혼합물을 여과하여 아세톤을 증발시키고 얻어진 잔사를 에테르에 용해시킨후 에테르용액에 2% 수산화나트륨 용액을 가하여 에테르층을 물로 세척하고, 황산나트륨상에서 건조후 에테르를 증발시킨 결과 유상의 2,4-비스-(β-메틸-2-부테닐옥시)-벤즈알데히드 9g이 얻어졌다.15 g of calcium carbonate was added to a solution of 5 g of 2,4-dihydroxybenzaldehyde dissolved in 200 ml of acetone, the mixture was stirred at room temperature for 20 minutes, and then 12 g of 3-methyl-2-butenyl chloride was added dropwise thereto for 3 hours. After stirring, the reaction mixture was filtered to evaporate acetone, and the obtained residue was dissolved in ether. Then, 2% sodium hydroxide solution was added to the ether solution, the ether layer was washed with water, dried over sodium sulfate, and the ether was evaporated. 9 g of 2,4-bis- (β-methyl-2-butenyloxy) -benzaldehyde was obtained.
다음 실시예는 일반식(1)의 화합물 제법을 설명한 것이다.The following example illustrates the preparation of a compound of formula (1).
[실시예 1]Example 1
에탄올 5ml에 용해시킨 2-(에톡시 카보닐메톡시)-4-(3-메틸-2-부테닐옥시)-아세토페논 1.5g 및 4-(3-메틸-2-부테닐옥시)-벤즈알데히드 1.0g의 용액에 20% 수산화나트륨 용액 10ml을 가하고, 이 용액을 희염산으로 희석하여 생성된 침전을 물로 세척후 에탄올로 부터 재결정시킨 결과 담황색 침상결정의 2'-(카복시메톡시)-4,4'-비스-(3-메틸-2-부테닐옥시)-칼큰 1.7g이 얻어졌다.1.5 g of 2- (ethoxy carbonylmethoxy) -4- (3-methyl-2-butenyloxy) -acetophenone and 4- (3-methyl-2-butenyloxy) -benzaldehyde 1.0 dissolved in 5 ml of ethanol. 10 ml of 20% sodium hydroxide solution was added to the solution of g. The solution was diluted with dilute hydrochloric acid, and the precipitate formed was washed with water and recrystallized from ethanol. 2 '-(carboxymethoxy) -4,4' of pale yellow acicular crystal was obtained. 1.7 g of -bis- (3-methyl-2-butenyloxy) -calken was obtained.
융점 : 141-142℃Melting Point: 141-142 ℃
[실시예 2]Example 2
에탄올 10ml에 용해시킨 2-(메톡시 카보닐메톡시)-4-(-3-메틸-2-부테닐옥시)-아세토페논 1.5g 및 2-(-3-메틸-2-부테닐옥시)-벤즈알데히드 1.0g의 용액에 20% 수산화칼리움용액 10ml를 가하고, 이 용액을 2시간동안 환류시킨후 반응혼합물을 희염산으로 증발시켜 얻어진 잔사를 에탄올로 부터 재결정시킨 결과 담황색 침상결정의 2-'(카복시메톡시)-2,4'-비스-(-3-메틸-2-부테닐옥시)-칼콘 1.7g이 얻어졌다. 융점 : 78-80℃2- (methoxycarbonylmethoxy) -4-(-3-methyl-2-butenyloxy) -acetophenone 1.5 g and 2-(-3-methyl-2-butenyloxy)-dissolved in 10 ml of ethanol 10 ml of 20% potassium hydroxide solution was added to a solution of 1.0 g of benzaldehyde, and this solution was refluxed for 2 hours, and the residue obtained by evaporation of the reaction mixture with dilute hydrochloric acid was recrystallized from ethanol. 1.7 g of methoxy) -2,4'-bis-(-3-methyl-2-butenyloxy) -chalcone were obtained. Melting Point: 78-80 ℃
[실시예 3]Example 3
에탄올 10ml에 용해시킨 2-(카복시메톡시)-4-(-3-메틸-2-부테닐옥시)-아세토페논 2.3g 및 벤즈알데히드 0.8g의 용액에 50% 수산화칼리움용액 15ml을 가하고, 이 용액을 25℃에서 3시간동안 교반한후 반응혼합물을 희염산으로 희석하여 얻어진 황색결정을 물로 세척하여 n-헥산-벤젠으로 부터 재결정시킨 결과 황색 침상 결정의 2'-(카복시메틸)-4'-(-3-메틸-2-부테닐옥시)-칼콘 2.0g이 얻어졌다.15 ml of 50% potassium hydroxide solution was added to a solution of 2.3 g of 2- (carboxymethoxy) -4-(-3-methyl-2-butenyloxy) -acetophenone and 0.8 g of benzaldehyde dissolved in 10 ml of ethanol. The solution was stirred at 25 ° C. for 3 hours, and the reaction mixture was diluted with dilute hydrochloric acid. The yellow crystals thus obtained were washed with water and recrystallized from n-hexane-benzene to give 2 '-(carboxymethyl) -4'- as a yellow acicular crystal. 2.0 g of (-3-methyl-2-butenyloxy) -chalcone were obtained.
융점 : 112-114℃Melting Point: 112-114 ℃
[실시예 4]Example 4
에탄올 30ml에 용해시킨 2-(에톡시카보닐메톡시)-아세토페논 1g 및 2,4-비스-(-3-메틸-2-부테닐옥시)-벤즈알데히드 1.2g의 용액에 50% 수산화칼리움용액 7ml를 가하고, 이 용액을 실온에서 4시간동안 교반한후 반응혼합물을 희염산으로 산성화하여 에테르로 추출하고, 에테르를 증발시켜 얻어진 잔사를 벤질으로 부터 재결정시킨 결과 담황색 침상결정의 2'-(카복시메톡시)-2,4-비스-(-3-메틸-2-부테닐옥시)-벤즈알데히드 1.5g이 얻어졌다. 융점 : 81-83℃50% potassium hydroxide solution in a solution of 1 g of 2- (ethoxycarbonylmethoxy) -acetophenone and 1.2 g of 2,4-bis-(-3-methyl-2-butenyloxy) -benzaldehyde dissolved in 30 ml of ethanol 7 ml was added, the solution was stirred at room temperature for 4 hours, the reaction mixture was acidified with dilute hydrochloric acid, extracted with ether, and the residue obtained by evaporation of ether was recrystallized from benzyl. 1.5 g of oxy) -2,4-bis-(-3-methyl-2-butenyloxy) -benzaldehyde was obtained. Melting Point: 81-83 ℃
[실시예 5]Example 5
에탄올 17ml에 용해시킨 2-(에톡시 카보닐메톡시)-아세토페논 1.5g 및 4-(-3-메틸-2-부테닐옥시)-벤즈알데히드 1.3g의 용액에 50% 수산화칼리움용액 17ml를 가하고, 이 용액을 실온에서 5시간동안 교반한 후, 반응혼합물을 희염산으로 희석하여 침전된 유상물질을 물로 세척하여 에테르로 추출하고, 에테르를 증발시켜 얻어진 잔사를 벤젠으로 부터 재결정시킨 결과 황색침상결정의 2'-(카복시메틸)-4-(-3-메틸-2-부테닐옥시)-칼콘 1.1g이 얻어졌다. 융점 : 141-142℃17 ml of 50% potassium hydroxide solution was added to a solution of 1.5 g of 2- (ethoxy carbonylmethoxy) -acetophenone and 1.3 g of 4-(-3-methyl-2-butenyloxy) -benzaldehyde dissolved in 17 ml of ethanol. After stirring for 5 hours at room temperature, the reaction mixture was diluted with dilute hydrochloric acid, the precipitated oil was washed with water, extracted with ether, and the residue obtained by evaporation of ether was recrystallized from benzene. 1.1 g of 2 '-(carboxymethyl) -4-(-3-methyl-2-butenyloxy) -chalcone were obtained. Melting Point: 141-142 ℃
[실시예 6]Example 6
에탄올 25ml에 용해시킨 2-(에톡시 카보닐메톡시)-아세토페논 1.2g 및 2-(-3-메틸-2-부테닐옥시)-벤즈알데히드 1g의 용액에 50% 수산화칼리움 7ml을 가하고, 이 용액을 50℃에서 2시간동안 교반한후, 반응혼합물을 희염산으로 산성화하여 에테르로 추출하고 에테르를 증발시켜 얻어진 잔사를 n-헥산-벤젠으로 부터 재결정시킨 결과 담황색 침상결정의 2'-(카복시메톡시)-2-(-3-메틸-2-부테닐옥시)-칼콘 1.5g이 얻어졌다. 융점 : 80-81℃To a solution of 1.2 g of 2- (ethoxy carbonylmethoxy) -acetophenone and 1 g of 2-(-3-methyl-2-butenyloxy) -benzaldehyde dissolved in 25 ml of ethanol, 7 ml of 50% calcium hydroxide was added. After the solution was stirred at 50 ° C. for 2 hours, the reaction mixture was acidified with dilute hydrochloric acid, extracted with ether, and the residue obtained by evaporation of the ether was recrystallized from n-hexane-benzene to obtain 2 ′-(carboxymethy) as pale yellow acicular crystal. 1.5 g of oxy) -2-(-3-methyl-2-butenyloxy) -chalcone was obtained. Melting Point: 80-81 ℃
다음 실험은 흡수율과 생리작용의 측정을 위한 생물학적 효력검정방법을 설명한 것이다.The following experiments describe biological potency assays for the measurement of absorption and physiology.
[시험 1][Exam 1]
위스타(wistar) 혈통의 수컷쥐를 24시간동안 단식시키고 에테르 마취하에 복벽(腹壁)을 중심선에 따라 절개한 다음, 유문부(幽門部)와 유문부로 부터 4cm 말초부를 각각 결찰시켜 맹검색(blind sack)을 만들었다. 이 시험용액(0.5% 카복시메틸 셀룰로오스-나트륨용액중에 현탁시킨 시험약제 100mg/kg의 용액)을 상기 맹검색내에 주사하고, 투여후 3시간후에 맹검색을 제거하고 잔여약제를 측정하여 시험약제의 흡수율을 결정하였다.Wistar male rats were fasted for 24 hours, the abdominal wall was cut along the centerline under ether anesthesia, and ligated 4 cm from the pyloric and pyloric regions, respectively, blind sack. ) This test solution (100 mg / kg of the test drug suspended in 0.5% carboxymethyl cellulose-sodium solution) was injected into the blind search, the blind search was removed 3 hours after administration, and the residual drug was measured to determine the absorption rate of the test drug. Was determined.
[시험 2][Exam 2]
본 발명 화합물의 항위궤양작용은 다까기(Takagi)의 초산궤양법(일본 약리학회지, 19,418(1969)에 따라 시험하였다. 체중 230-250g 되는 돈류(Donryu)혈통의 수컷쥐를 사용하여 초산의 점막내 주사로 유발된 만성위궤양에 대한 본 발명 화합물의 치유효과를 시험하였다. 상기 쥐를 에테르 마취하에 개복수술하고, 유문공동의 점막종과 혈장 사이에 20% 초산 0.01ml를 주사하였다. 수술후 복부를 복개하고 쥐에게 정상적으로 급식하였다. 시험약제는 수술후 2-10일간 1일 2회씩 주기적으로 투여하였으며, 쥐는 궤양의 치유 과정을 평가하기 위하여 수술후 12일째 희생시켰다. 각 쥐의 위(胃)를 제거하여 1% 포르말린 용액 15ml으로 채우고, 약 10분간 동일용액에 놓아 브로디이(Brodie)법(위장학, 38,353(1960)에 따라 위벽의 외층을 응고시켰다.Anti-gastric ulceration of the compound of the present invention was tested according to the method of acetic ulceration of Takagi (Japanese Journal of Pharmacology, 19,418 (1969). Point of acetic acid using male rats of Donryu lineage weighing 230-250 g. The healing effect of the compound of the present invention on the chronic gastric ulcer induced by intramembrane injection was tested The rats were laparoscopically operated under ether anesthesia, and 0.01 ml of 20% acetic acid was injected between the pyloric mucosa and plasma. The drug was administered twice a day for 2-10 days after surgery, and the rats were sacrificed on day 12 postoperatively to evaluate the healing process of ulcers. 15 ml of a 1% formalin solution was filled and placed in the same solution for about 10 minutes to coagulate the outer layer of the gastric wall according to Brodie method (Gastroscopy, 38,353 (1960)).
다음에 위를 대곡선에 따라 절개하고 위에서의 손상부분을 관찰하였다. 발병된 궤양의 부위를 궤양인덱스로 정하였다.The stomach was then incised along a large curve and the damage to the stomach was observed. The site of the affected ulcer was defined as the ulcer index.
이 궤양인덱스를 사용하여 궤양의 치유율이 다음 일반식으로 부터 산출되였다.Using this ulcer index, the healing rate of the ulcer was calculated from the following general formula.
치유율(%)=100(C-S)/CHealing Rate (%) = 100 (C-S) / C
위식에서, C는 대조용의 궤양인덱스이고, S는 샘플의 궤양인덱스이다.In the above formula, C is the control ulcer index and S is the ulcer index of the sample.
이와 같이 하여 얻어진 각 화합물의 치유율은 다음 표 1에 표시된 바와 같다.The cure rate of each compound thus obtained is as shown in Table 1 below.
[시험 3][Exam 3]
또다른 항위궤양작용시험은 세이(shay) 궤양법(위장학, 5,43,(1945))에 따라 행하였다.Another anti-gastric ulceration test was conducted according to the shay ulceration method (Gastroscopy, 5,43, (1945)).
체중 200-230g 되는 돈류혈통의 수컷쥐를 사용하여 유문결찰로 유발된 소위 세이궤양(shay's ulcer)에 대한 본 발명 화합물의 예방효과를 시험하였다. 수술전에 쥐를 물 이외는 48시간동안 단식시키고, 에테르 마취하에 쥐의 복부중앙선을 절개하여 유문부를 결찰한 다음, 복부를 복개하고 시험약제를 복강내에 투여하였다. 수술후 15시간이 경과한 후에 수출한 쥐를 에테르를 흡입시켜 치사시켰다. 다음에 식도를 결찰하고, 위를 주의하여 제거하였다. 위액의 용량을 측정하고 전부위(전부위) 부분에서의 손상을 육안으로 검사하였다. 다음에 궤양 및 미란부분을 측정하고 양자의 총합을 궤양인덱스로 정하였다.A male rat of a pig bloodline weighing 200-230 g was used to test the prophylactic effect of the compound of the present invention against so-called shay's ulcer caused by pyloric ligation. Before surgery, the rats were fasted for 48 hours except water, and the aortic midline of the rat was incised under ether anesthesia to ligation the pyloric region, and then the abdomen was abdominally administered with the test drug intraperitoneally. After 15 hours, the exported mice were killed by inhaling ether. The esophagus was then ligation and the stomach was carefully removed. The dose of gastric juice was measured and the damage at the forearm site was visually examined. The ulcer and erosion were then measured and the sum of both was determined as the ulcer index.
이 궤양인덱스를 사용하여 다음 일반식으로 부터 궤양의 예방율을 산출하였다.The ulcer index was used to calculate the prevention rate of the ulcer from the following general formula.
예방율(%)=100(C-S)/CPrevention rate (%) = 100 (C-S) / C
위 식에서, C는 대조용의 궤양인덱스이고, S는 샘플의 궤양인덱스이다.Where C is the control ulcer index and S is the ulcer index of the sample.
이와같이 하여 얻어진 각 화합물의 궤양인덱스 및 궤양의 예방율과 동일한 방법으로 산출한 위액분비의 예방율(%)은 다음 표 1에 요약된 바와 같다.The prevention rate (%) of gastric secretion calculated in the same manner as the ulcer index and the ulcer prevention rate of each compound thus obtained are summarized in Table 1 below.
[시험 4][Exam 4]
본 발명 화합물의 항위궤양작용은 다까기의 스트레스궤양법(일본 약리학회지 18,9(1968))에 따라 시험하였다.The anti-gastric ulcer action of the compound of the present invention was tested according to the stress ulceration method of the Japanese (Japanese Journal of Pharmacology 18,9 (1968)).
체중 260-300g 되는 돈류혈통의 수컷 쥐를 사용하여 억압 및 수침(水浸)으로 유발된 위궤양에 대한 본 발명 화합물의 예방 효과를 시험하였다. 쥐는 스트레스 케이지에 놓아 움직이지 못하게 하고 7시간동안 23℃에서 수욕중에서 쥐의 싸이포이드(xyphiod)에 수직으로 침지하였다. 시험약제는 억류하기 30분전에 복강내로 투여하였다.The male rats of the pig bloodline weighing 260-300 g were used to test the prophylactic effect of the compound of the present invention on gastric ulcer induced by repression and acupuncture. The rats were placed in a stress cage, immobilized and immersed vertically in the rat's xyphiod in a water bath at 23 ° C. for 7 hours. Test agents were administered intraperitoneally 30 minutes prior to detention.
스트레스기간이 끝날때에 쥐를 수욕으로 부터 제거하여 스트레스 케이지로 부터 해방시키고 강타하여 치사시켰다. 다음에 위를 제거하여 1% 포르말린용액 15ml로 팽창시키고 브로디법에 따라 위벽의 외층을 응고시킨 다음, 위를 대곡선에 따라 절개하여 손상부분을 육안으로 검사하였다. 귀양 및 미란부위를 측정하고 양자의 총합을 궤양인덱스로서 정하였다.At the end of the stress period, the rats were removed from the bath, freed from the stress cage, and struck and killed. Next, the stomach was removed, expanded to 15 ml of 1% formalin solution, and the outer layer of the stomach wall was solidified according to Brody's method. The stomach was cut along the curve to visually inspect the damaged area. Guiyang and erosion sites were measured and the sum of both was determined as the ulcer index.
시험 3에 기술된 일반식으로 부터 예방율(%)을 산출하였는바 다음 표 1에 표시된 바와같다.The% prevention was calculated from the general formula described in test 3, as shown in Table 1 below.
[시험 5][Exam 5]
때때로 위궤양을 유발하는 약제로서, 아스피린을 선택하여 본 발명 화합물의 항위궤양작용을 시험하였다.As a medicament that sometimes causes gastric ulcers, aspirin was selected to test the antigastric ulcer activity of the compounds of the invention.
체중 200-300g 되는 돈류혈통의 수컷 쥐를 사용하여 아스피린으로 유발된 위궤양에 대한 예방효과를 시험하였다. 쥐는 각각에게 2시간 간격으로 3회 주기적으로 아스피린 200mg/kg을 투여하여 처리하였으며 시험약제는 최초 아스피린을 투여하기 30분 전에 주기적으로 투여하였다. 최종적으로 아스피린을 투여하고 2시간후에 쥐를 강타하여 희생시키고, 각 위를 제거하여 1% 포르말린용액 15ml로 팽창시켜서 1% 포르말린용액중에 넣었다. 10분후에 위를 대곡선에 따라 절개하여 궤양 및 미란부위를 측정하였다. 양자의 총합을 궤양인덱스로 정하고 시험 2에 기술된 방법에 따라 각 예방율(%)을 산출하였는바, 다음 표 1에 표시된 바와 같다.A male rat of a pig bloodline of 200-300 g body weight was used to examine the protective effect against aspirin-induced gastric ulcer. The rats were treated with 200 mg / kg of aspirin three times at 2 hour intervals each, and the test drug was periodically administered 30 minutes before the first aspirin. Finally, 2 hours after the administration of aspirin, the rats were struck and sacrificed. Each stomach was removed, expanded to 15 ml of 1% formalin solution, and placed in 1% formalin solution. After 10 minutes, the stomach was incised along a large curve to measure ulceration and erosion. The sum of both was determined as the ulcer index and the percentage of each prevention was calculated according to the method described in Test 2. As shown in Table 1 below.
[시험 6][Exam 6]
본 발명 화합물의 항위궤양작용은 히스타민 궤양법에 따라 시험하였다.Anti-gastric ulceration of the compounds of the present invention was tested according to histamine ulceration.
체중 360-400g 되는 하트레이(Hartley) 혈통의 수컷쥐를 24시간동안 단식시키고, 트리페레나민 염산염(10mg/kg)의 근육내 투여후 15분 경과후에 히스타민 염산염(50mg/kg)을 피하투여하였다. 다음에 쥐에게 계속 3일간 0.4% 카복시메틸셀룰로오스-나트륨용액에 현탁한 약제를 1일 100mg/kg의 양으로 경구 투여 한다음, 궤양의 처치후 4일째에 쥐의 두부를 강타하여 희생시키고, 1% 포르말린처리후에 위를 대곡선에 따라 절개하여 위에서의 손상을 검사하였다.Male rats of Hartley lineage weighing 360-400 g were fasted for 24 hours and subcutaneously administered with histamine hydrochloride (50 mg / kg) 15 minutes after intramuscular administration of triprenamine hydrochloride (10 mg / kg). . Next, the mice were orally administered with the drug suspended in 0.4% carboxymethylcellulose-sodium solution for 3 days in an amount of 100 mg / kg per day, and then struck and sacrificed to the head of the rat 4 days after the treatment of the ulcer, After% formalin treatment, the stomach was incised along the curve to check for damage to the stomach.
시험 2에 기술된 일반식으로 부터 각 치유율(%)을 산출하였는바, 다음 표 1에 표시된 바와 같다Each healing rate (%) was calculated from the general formula described in Test 2, as shown in Table 1 below.
[시험 7][Exam 7]
본 발명 화합물의 항위궤양 및 항십이지궤양작용은 시스테아민 궤양법에 따라 시험하였다.Anti-gastric and anti-duodenal ulceration of the compounds of the present invention were tested according to the cysteamine ulcer method.
체중 200-220g 되는 돈류혈통의 수컷 쥐를 24시간동안 단식시키고, 시험약제의 투여후 30분 경과후에 시스테아민 염산염(400mg/kg)을 피하투여하였다. 시험약제의 투여후 18시간 경과후에 쥐를 희생시키고, 위를 위궤양 및 십이지장궤양에 대하여 검사하였다. 궤양인덱스는 손상부위(mm2)의 총합으로 나타내었다.Male rats of the piglet strain weighing 200-220 g were fasted for 24 hours, and subcutaneously administered with cysteamine hydrochloride (400 mg / kg) 30 minutes after administration of the test drug. Mice were sacrificed 18 hours after administration of the test agent and the stomach was examined for gastric ulcer and duodenal ulcer. The ulcer index was expressed as the sum of the damage sites (mm 2 ).
시험 3에 기술된 일반식으로 부터 각 예방율(%)을 산출하였는바, 다음 표 1에 기술된 바와 같다.Each prevention rate (%) was calculated from the general formula described in Test 3, as described in Table 1 below.
[표 1]TABLE 1
쥐에서의 흡수율:초산궤양 및 히스타민궤양의 치유율 및 세이궤양(shay,s ulcer),스트레스궤양, 아스피린-유발궤양, 시스테아민궤양(위 및 십이지장)의 예방율 및 쥐에서 세이궤양의 경우에 위액분비의 예방율.Absorption rate in rats: cure rate of acetic ulcer and histamine ulcer and shay, sulcer, stress ulcer, aspirin-induced ulcer, prevention of cysteamine ulcer (gastric and duodenal) and in case of sei ulcer in rat Prevention rate of gastric secretion.
p75p75
화합물 A : 4,4-비스-(3-메틸-2-부테닐옥시)-칼콘Compound A: 4,4-bis- (3-methyl-2-butenyloxy) -chalcone
화합물 B : 2'-메톡시-4,4'-비스-(3-메틸-2-부테닐옥시)-칼콘Compound B: 2'-methoxy-4,4'-bis- (3-methyl-2-butenyloxy) -chalcone
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| Application Number | Priority Date | Filing Date | Title |
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| KR7700273A KR810000953B1 (en) | 1977-02-09 | 1977-02-09 | Method for the preparation of 2'-(carboxymethoxy)-chalcones |
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| Application Number | Priority Date | Filing Date | Title |
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| KR7700273A KR810000953B1 (en) | 1977-02-09 | 1977-02-09 | Method for the preparation of 2'-(carboxymethoxy)-chalcones |
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| Publication Number | Publication Date |
|---|---|
| KR810000953B1 true KR810000953B1 (en) | 1981-08-24 |
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| KR7700273A KR810000953B1 (en) | 1977-02-09 | 1977-02-09 | Method for the preparation of 2'-(carboxymethoxy)-chalcones |
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| KR (1) | KR810000953B1 (en) |
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1977
- 1977-02-09 KR KR7700273A patent/KR810000953B1/en active
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